20.7 Physical Properties of Esters TABLE 20.4 Preparation of Esters Reaction(section) and General equation and specific example From carboxylic acids(Sections 15.8 and 19. 14)In the presence of an acid catalyst, alcohols and OH R'OH carboxylic acids react to form Carboxylic Alcohol Este Water n ester and water. This is the Fischer esterification CHaCH, COH +CHa CH2 CH2 CH,OH H2SO CH3CH, COCH2 CH2CH2 CH3 H2o Butyl propanoate Water From acyl chlorides(Sections 15.8 and 20.3)Alcohols react with acyl chlorides by nucleo RCCI R'OH+ →RCOR'+ hilic acyl substitution to yield sters. These reactions are typi cally performed in the presence of a weak base such as pyri- Alcohol Pyridine chloride O2N O2N CCI +( CH3)2 CHCH,OHpyrid OCH O2N alcohol 3.5-dinitrobenzoate From carboxylic acid anhy. dries(Sections 15.8 and 20.5) Acyl transfer from an acid RCOCR+R'OH→>RCoR′+RCOH anhydride to an alcohol is a Alcohol Ester boxvlic standard method for the prep- anhydride aration of esters the reaction is subject to catalysis by either CHO acids(H2SO4)or bases(pyri CHaCOCCHa+ alcohol acetate Baeyer-Villiger oxidation of ketones(Section 17.16) Ketones are converted to esters RCR′+R"coOH RCOH on treatment with peroxy Ketone Perox Ester Carboxylic acids. The reaction proceeds by migration of the group R' from carbon to oxygen. It is the more highly substituted group CF:CO,OH 9 CH3co that migrates Methyl ketones give acetate esters Cyclopropyl methyl ketone acetate(53%) Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
20.7 Physical Properties of Esters 789 TABLE 20.4 Preparation of Esters Reaction (section) and comments From carboxylic acids (Sections 15.8 and 19.14) In the presence of an acid catalyst, alcohols and carboxylic acids react to form an ester and water. This is the Fischer esterification. From acyl chlorides (Sections 15.8 and 20.3) Alcohols react with acyl chlorides by nucleophilic acyl substitution to yield esters. These reactions are typically performed in the presence of a weak base such as pyridine. From carboxylic acid anhydrides (Sections 15.8 and 20.5) Acyl transfer from an acid anhydride to an alcohol is a standard method for the preparation of esters. The reaction is subject to catalysis by either acids (H2SO4) or bases (pyridine). Baeyer-Villiger oxidation of ketones (Section 17.16) Ketones are converted to esters on treatment with peroxy acids. The reaction proceeds by migration of the group R from carbon to oxygen. It is the more highly substituted group that migrates. Methyl ketones give acetate esters. General equation and specific example H2SO4 Propanoic acid CH3CH2COH O X 1-Butanol CH3CH2CH2CH2OH Water H2O Butyl propanoate (85%) CH3CH2COCH2CH2CH2CH3 O X Carboxylic acid RCOH O X Ester RCOR O X ROH Alcohol H2O Water H Acyl chloride RCCl O X Ester RCOR O X ROH Alcohol N Pyridine Pyridinium chloride N H Cl pyridine CCl O2N O2N O X 3,5-Dinitrobenzoyl chloride COCH2CH(CH3)2 O2N O2N O X Isobutyl 3,5-dinitrobenzoate (85%) (CH3)2CHCH2OH Isobutyl alcohol Acid anhydride RCOCR O X O X ROH Alcohol Ester RCOR O X Carboxylic acid RCOH O X pyridine CH2OH CH3O m-Methoxybenzyl alcohol CH2OCCH3 CH3O O X m-Methoxybenzyl acetate (99%) Acetic anhydride CH3COCCH3 O X O X Ketone RCR O X Peroxy acid RCOOH O X Carboxylic acid RCOH O X Ester RCOR O X CF3CO2OH Cyclopropyl methyl ketone CH3C O X Cyclopropyl acetate (53%) CH3CO O X Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution CH3CHCH, CH3 CH3COCH CH3 CHCH, CH3 2-Methylbutane: Methyl acetate: 2-Butanol mol wt 72, bp 28C mol wt 74, bp 57.C mol wt 74, bp 99C Esters can participate in hydrogen bonds with substances that contain hydroxyl groups(water, alcohols, carboxylic acids ). This confers some measure of water solubil- ity on low-molecular-weight esters; methyl acetate, for example, dissolves in water to the extent of 33 g/100 mL. Water solubility decreases as the carbon content of the ester increases. Fats and oils, the glycerol esters of long-chain carboxylic acids, are practically insoluble in water 20. 8 REACTIONS OF ESTERS: A REVIEW AND A PREVIEW The reaction of esters with Grignard reagents and with lithium aluminum hydride, both useful in the synthesis of alcohols, were described earlier. They are reviewed in Table 20 ucleophilic acyl substitutions at the ester carbonyl group are summarized in Table 20.6. Esters are less reactive than acyl chlorides and acid anhydrides. Nucleophilic acyl substitution in esters, especially ester hydrolysis, has been extensively investigated from a mechanistic perspective. Indeed, much of what we know concerning the general topi TABLE 20.5 Summary of Reactions of Esters Discussed in Earlier Chapters Reaction(section) and General equation and specific example Reaction with Grignard reagents(Section 14.10) Esters react with two RcoR′+2RMgX RCR+ ROH equivalents of a Grignard reagent to produce teri- ry alcohols. Two of the Ester Grignard Tertiary Alcohol groups bonded to the car alcohol bon that bears the hydroxyl group in the ter- ether ary alcohol are derived >-COCH2CH3 2CH3 Mg 2. Ho) CCH3 CH3CH2OH from the Grignard Ethyl Methylmagne 2-Cyclopropyl-2 Ethano Reduction with lithium 1. LiAIHa tion 15.3)Lithium alumi. RCOR2 H0 RCH2 OH+ ROH num hydride cleaves Alcohol esters to yield two alco- alcohol COCH2 CH3 CH2OH CH3CH2OH Ethyl benzoate Benzyl alcohol(90%) alcohol Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Esters can participate in hydrogen bonds with substances that contain hydroxyl groups (water, alcohols, carboxylic acids). This confers some measure of water solubility on low-molecular-weight esters; methyl acetate, for example, dissolves in water to the extent of 33 g/100 mL. Water solubility decreases as the carbon content of the ester increases. Fats and oils, the glycerol esters of long-chain carboxylic acids, are practically insoluble in water. 20.8 REACTIONS OF ESTERS: A REVIEW AND A PREVIEW The reaction of esters with Grignard reagents and with lithium aluminum hydride, both useful in the synthesis of alcohols, were described earlier. They are reviewed in Table 20.5. Nucleophilic acyl substitutions at the ester carbonyl group are summarized in Table 20.6. Esters are less reactive than acyl chlorides and acid anhydrides. Nucleophilic acyl substitution in esters, especially ester hydrolysis, has been extensively investigated from a mechanistic perspective. Indeed, much of what we know concerning the general topic 2-Methylbutane: mol wt 72, bp 28°C CH3CHCH2CH3 CH3 2-Butanol: mol wt 74, bp 99°C CH3CHCH2CH3 OH Methyl acetate: mol wt 74, bp 57°C CH3COCH3 O 790 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution TABLE 20.5 Summary of Reactions of Esters Discussed in Earlier Chapters Reaction (section) and comments Reaction with Grignard reagents (Section 14.10) Esters react with two equivalents of a Grignard reagent to produce tertiary alcohols. Two of the groups bonded to the carbon that bears the hydroxyl group in the tertiary alcohol are derived from the Grignard reagent. Reduction with lithium aluminum hydride (Section 15.3) Lithium aluminum hydride cleaves esters to yield two alcohols. General equation and specific example Ester RCOR O X Tertiary alcohol RCR W W OH R 2RMgX Grignard reagent ROH Alcohol 1. diethyl ether 2. H3O 2CH3MgI Methylmagnesium iodide CH3CH2OH Ethanol 1. diethyl ether 2. H3O Ethyl cyclopropanecarboxylate COCH2CH3 O X 2-Cyclopropyl-2- propanol (93%) CCH3 CH3 W W OH Ester RCOR O X ROH Alcohol RCH2OH Primary alcohol 1. LiAlH4 2. H2O COCH2CH3 O X Ethyl benzoate CH2OH Benzyl alcohol (90%) CH3CH2OH Ethyl alcohol 1. LiAlH4 2. H2O Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
20.9 Acid-Catalyzed Ester Hydrolysis TABLE 20.6 Conversion of Esters to Other Carboxylic Acid Derivatives Reaction(section) and comments General equation and specific example Reaction with ammonia and amines sec tion 20.13)Esters react with ammonia and amines to form amides. Methyl and ethyl RCOR’+R2NH RCNR2+ ROH esters are the most reactive Ester Amine FCH2 COCH2 CH3+ NH3 FCH2 CNH2 CH3CH2OH Ethyl Ammonia Ethanol fluoroacetate (90%) Hydrolysis(Sections 20.9 and 20. 10)Ester or by bases. Acid-catalyzed hydrolysis is an RCOR+ H2o RCOH R'OH equilibrium- controlled process, the reverse Ester Water Carboxyl Alcohol of the Fischer esterification. Hydrolysis in base is irreversible and is the method usual ly chosen for preparative purposes O2N O2N 1. HO. Nao COCH3 COH+ CH3OH Methyl m-Nitrobenzo Methanol m-nitrobenzoate acid(90-96% of nucleophilic acyl substitution comes from studies carried out on esters. The follow ing sections describe those mechanistic studies 20.9 ACID-CATALYZED ESTER HYDROLYSIS Ester hydrolysis is the most studied and best understood of all nucleophilic acyl substi- tutions. Esters are fairly stable in neutral aqueous media but are cleaved when heated with water in the presence of strong acids or bases. The hydrolysis of esters in dilute aqueous acid is the reverse of the Fischer esterification(Sections 15.8 and 19.14): RCor ho h rcoh r'Oh Ester Water Carboxylic Alcohol When esterification is the objective, water is removed from the reaction mixture to encourage ester formation. When ester hydrolysis is the objective, the reaction is carried out in the presence of a generous excess of water -CHCOCH, CH3 H,O CHCOH CHi CH,OH 2-Chloro-2-phenylacetic Ethyl 2-chloro-2-pher acid(80-82%) Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
20.9 Acid-Catalyzed Ester Hydrolysis 791 TABLE 20.6 Conversion of Esters to Other Carboxylic Acid Derivatives Reaction (section) and comments Reaction with ammonia and amines (Section 20.13) Esters react with ammonia and amines to form amides. Methyl and ethyl esters are the most reactive. Hydrolysis (Sections 20.9 and 20.10) Ester hydrolysis may be catalyzed either by acids or by bases. Acid-catalyzed hydrolysis is an equilibrium-controlled process, the reverse of the Fischer esterification. Hydrolysis in base is irreversible and is the method usually chosen for preparative purposes. General equation and specific example Ester RCOR O X Amide RCNR 2 O X R 2NH Amine ROH Alcohol Ester RCOR O X Carboxylic acid RCOH O X H2O Water ROH Alcohol Fluoroacetamide (90%) FCH2CNH2 O X Ethyl fluoroacetate FCH2COCH2CH3 O X H2O NH3 Ammonia CH3CH2OH Ethanol 1. H2O, NaOH 2. H COCH3 O2N O X Methyl m-nitrobenzoate COH O2N O X m-Nitrobenzoic acid (90–96%) CH3OH Methanol of nucleophilic acyl substitution comes from studies carried out on esters. The following sections describe those mechanistic studies. 20.9 ACID-CATALYZED ESTER HYDROLYSIS Ester hydrolysis is the most studied and best understood of all nucleophilic acyl substitutions. Esters are fairly stable in neutral aqueous media but are cleaved when heated with water in the presence of strong acids or bases. The hydrolysis of esters in dilute aqueous acid is the reverse of the Fischer esterification (Sections 15.8 and 19.14): When esterification is the objective, water is removed from the reaction mixture to encourage ester formation. When ester hydrolysis is the objective, the reaction is carried out in the presence of a generous excess of water. CHCOCH2CH3 O Cl Ethyl 2-chloro-2-phenylacetate H2O Water HCl heat CHCOH O Cl 2-Chloro-2-phenylacetic acid (80–82%) CH3CH2OH Ethyl alcohol RCOR O X Ester H2O Water ROH Carboxylic Alcohol acid RCOH O H X Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution PROBLEM 20.9 The compound having the structure shown was heated with dilute sulfuric acid to give a product having the molecular formula C5H12O3 in 63-71% yield Propose a reasonable structure for this product. what other organic compound is formed in this reaction CH3COCH2 CHCH2 CH2CH2OCCH3 0,H505,? The mechanism of acid-catalyzed ester hydrolysis is presented in Figure 20.4. It is precisely the reverse of the mechanism given for acid-catalyzed ester formation in Sec- tion 19.14. Like other nucleophilic acyl substitutions, it proceeds in two stages. A tetra hedral intermediate is formed in the first stage. and this tetrahedral intermediate disso- ciates to products in the second stage a key feature of the first stage is the site at which the starting ester is protonated Protonation of the carbonyl oxygen, as shown in step l of Figure 20.4, gives a cation that is stabilized by electron delocalization. The alternative site of protonation, the alkoxy oxygen, gives rise to a much less stable cation Step 1: Protonation of the carbonyl oxygen of the ester H OR Ester Hydronium Protonated form of ester Step 2: Nucleophilic addition of water to protonated form of ester H P RC-OR OR′ Protonated form of ester Step 3: Deprotonation of the oxonium ion to give the neutral form of the FIGURE 20.4 The mecha- nism of acid-catalyze hydrolysis Steps 1 through 3 show the formation of the tetrahedral intermediate Hydronium Dissociation of the tetrahe- dral intermediate is shown in steps 4 through 6 -Cont Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
PROBLEM 20.9 The compound having the structure shown was heated with dilute sulfuric acid to give a product having the molecular formula C5H12O3 in 63–71% yield. Propose a reasonable structure for this product. What other organic compound is formed in this reaction? The mechanism of acid-catalyzed ester hydrolysis is presented in Figure 20.4. It is precisely the reverse of the mechanism given for acid-catalyzed ester formation in Section 19.14. Like other nucleophilic acyl substitutions, it proceeds in two stages. A tetrahedral intermediate is formed in the first stage, and this tetrahedral intermediate dissociates to products in the second stage. A key feature of the first stage is the site at which the starting ester is protonated. Protonation of the carbonyl oxygen, as shown in step 1 of Figure 20.4, gives a cation that is stabilized by electron delocalization. The alternative site of protonation, the alkoxy oxygen, gives rise to a much less stable cation. CH3COCH2CHCH2CH2CH2OCCH3 OCCH3 O O O ? H2O, H2SO4 heat 792 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution Step 1: Protonation of the carbonyl oxygen of the ester H H O H OR O Ester RC Hydronium ion OR O RC H Protonated form of ester H H O Water Step 2: Nucleophilic addition of water to protonated form of ester O H H Water OR O RC H Protonated form of ester RC OR O H H OH Oxonium ion Step 3: Deprotonation of the oxonium ion to give the neutral form of the tetrahedral intermediate RC OR O H H OH Oxonium ion H H O Water RC OR OH OH Tetrahedral intermediate H H O H Hydronium ion X X X —Cont. FIGURE 20.4 The mechanism of acid-catalyzed ester hydrolysis. Steps 1 through 3 show the formation of the tetrahedral intermediate. Dissociation of the tetrahedral intermediate is shown in steps 4 through 6. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website